KR20170053150A - Composition for Skin Whitening Comprising Stipitalide as Active Ingredients - Google Patents
Composition for Skin Whitening Comprising Stipitalide as Active Ingredients Download PDFInfo
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- KR20170053150A KR20170053150A KR1020170023448A KR20170023448A KR20170053150A KR 20170053150 A KR20170053150 A KR 20170053150A KR 1020170023448 A KR1020170023448 A KR 1020170023448A KR 20170023448 A KR20170023448 A KR 20170023448A KR 20170053150 A KR20170053150 A KR 20170053150A
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- KR
- South Korea
- Prior art keywords
- composition
- stipitalide
- present
- active ingredient
- skin whitening
- Prior art date
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- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
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- A61Q17/02—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings containing insect repellants
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Abstract
Description
본 발명은 하기 화학식 1로 표시되는 곤충유래 곰팡이균으로부터 추출한 스티피탈리드를 유효성분으로 포함하는 구강 질환 예방 또는 치료용 약학 조성물 및 예방 또는 개선용 건강기능식품, 방부제 조성물 또는, 미백용 약학 조성물, 화장료 조성물 및 건강기능식품 조성물에 대한 것이다. The present invention relates to a pharmaceutical composition for preventing or treating oral diseases, comprising stipetalide extracted from an insect-derived fungus bacterium represented by the following formula (1) as an active ingredient, a health functional food for prevention or improvement, a preservative composition or a whitening pharmaceutical composition, A cosmetic composition and a health functional food composition.
[화학식 1][Chemical Formula 1]
치아 우식증, 치은염, 치주염, 구취 등과 같은 구강 질환은 근본적으로는 스트렙토코커스 뮤탄스(Steptococcus mutans), 포피로모나스 긴기발리스(Porphyromonas gingivalis), 프레보텔라 인터메디아(Prevotella intermedia), 액티노바실러스 액티노마이세템코미탄스(Actinobacillus actinomycetemcomitans), 칸디다 알비칸스(Candida albicans) 등과 같은 병원성 미생물을 포함하는, 칸디다속(Candida spp.)의 구강 병원균으로부터 주로 야기되는 것으로 알려져 있다.Oral diseases such as dental caries, gingivitis, periodontitis, bad breath, and the like are fundamentally derived from Streptococcus mutans, Porphyromonas gingivalis, Prevotella intermedia, Actinobacillus juice It is known to be caused mainly by oral pathogens of the genus Candida spp., Including pathogenic microorganisms such as Actinobacillus actinomycetemcomitans, Candida albicans and the like.
따라서, 종래에는 구강 질환을 치료하기 위하여 상기 구강 병원균들의 생장을 억제하거나 사멸시키는 방안에 대한 연구나 항균 물질에 대한 연구가 주를 이루어 왔다. 그러나 이러한 항균 물질들은 구강 내 유해한 병원균뿐만 아니라, 구강 내 유익한 균까지도 모두 제거하는 것이 대부분이며, 항균 물질의 과도한 사용으로 인하여 항균 물질에 대한 저항성이 증가하거나 유전적 변이가 일어나 내성이 생기는 구강 병원균들이 증가함에 따라 종래와 같은 항균 물질만을 이용하여서는 구강 질환의 예방 또는 치료에 한계가 있다.Therefore, in order to treat oral diseases, studies on inhibiting or killing the growth of oral pathogens or studies on antimicrobial substances have been made. However, most of these antimicrobial substances remove not only harmful pathogens in the oral cavity but also beneficial bacteria in the mouth. Oral pathogens that are resistant to antimicrobial substances due to excessive use of antimicrobial substances or resistant to genetic mutations There is a limit to the prevention or treatment of oral diseases using only conventional antimicrobial substances.
한편 방부제(Antiseptic: 防腐劑)란 물질의 부패를 막는 약제를 말한다. 동식물성 유기물이 미생물의 작용에 의해 부패하는 것을 막는 것이 방부이고, 보존을 목적으로 방부하기 위해서 첨가하는 약제가 방부제이다. 부패를 일으키는 미생물에는 진균류에 속하는 곰팡이, 효모와 하등미생물인 세균이 있다.Meanwhile, antiseptic (antiseptic) is a drug that prevents the decay of the material. It is a preservative to prevent the vegetable organic material from decaying due to the action of microorganisms, and the preservative is added to preserve it for the purpose of preservation. The microorganisms that cause decay include fungi, yeast, and other microorganisms belonging to fungi.
이러한 방부제는 일반적으로 식품, 화장품 또는 의약품 등의 변질을 막고 그것을 사용하거나 보존하는 동안에 그 순도를 유지시키기 위해서 첨가한다. 따라서 인체에 해가 없어야 한다는 것이 필수조건이고, 또 그 첨가로 인해 품질을 손상시키지 않아야 한다.Such preservatives are generally added to prevent deterioration of foods, cosmetics or pharmaceuticals and to maintain their purity during their use or preservation. Therefore, it is a prerequisite that there is no harm to the human body, and it should not deteriorate the quality due to the addition.
식품방부제는 식품보존제라고도 하며 음식물이 공기 중에 노출될 때 산화되는 것을 막아주거나 곰팡이나 박테리아 같은 미생물이 음식물을 부패시키는 것을 방지해야 한다. 종래 식품 방부제로는 프로피온산 칼슘, 벤조산 나트륨, 아질산 나트륨과 소르브산 등과 같은 화학 방부제가 사용되어 왔다. 프로피온산은 곰팡이가 생기는 것을 막아주며 빵 치즈 초콜릿 등에 사용한다. 벤조산 나트륨은 오렌지주스나 그레이프 프루트 주스에 첨가하면 미생물의 성장을 막는다. 아질산 나트륨은 육류에서 미생물이 자라는 것을 막아준다. 소르브산과 그 염은 특히 치즈에서 곰팡이나 효모가 자라는 것을 억제한다. 그러나 이러한 화학 방부제는 양이 초과되면 사람이나 가축에 모두 유해하므로 법(약사법 및 식품위생법)으로 그 사용이 규제되고 있다.Food preservatives, also called food preservatives, prevent food from being oxidized when exposed to air or prevent microbes such as molds and bacteria from spoiling food. Conventional food preservatives such as calcium propionate, sodium benzoate, sodium nitrite and sorbic acid have been used as chemical preservatives. Propionate prevents mold growth and is used in bread, cheese, and chocolate. Sodium benzoate prevents the growth of microorganisms when added to orange juice or grapefruit juice. Sodium nitrite prevents the growth of microorganisms in meat. Sorbic acid and its salts inhibit the growth of mold or yeast, especially in cheese. However, since these chemical preservatives are harmful to humans and livestock if their amounts are exceeded, their use is regulated by the Act (Pharmaceutical Affairs Law and Food Sanitation Act).
화장품 방부제는 화장품을 오랫동안 상온에서 보관할 수 있게 만든다. 화장품은 개봉 후 오래 두고 써야 하기 때문에 쉽게 변질되지 않도록 소비자 보호를 위해 방부제(보존)를 넣는다. 화장품에 주로 사용되는 방부제는 메틸 파라벤(Metyl Paraben), 에틸 파라벤(Ethyle Paraben), 프로필 파라벤(Propyl Paraben), 부틸 파라벤(Butyl Paraben), 쿼터늄-15(Quaternium-15), 이미다졸리디닐 우레아(Imidazolidinyl Urea) 등이다. 그러나 화장품은 평생을 두고 인체에 직접 사용하므로 미량의 방부제라 하더라도 인체에 적지 않은 영향을 미칠 수 있다. 실제 피부과 의사들은 피부 트러블 증상 때문에 병원을 찾은 환자의 70%는 그 원인이 화장품 독성(방부제 성분)이라고 말한다. 화장품에 함유된 방부제 성분이 알레르기 반응을 일으키거나 피부에 자극을 줄 수 있다. 최근에는 각종 화장품과 향수에 함유되고 있는 화학물질의 일종인 파라벤(parabens)이 인체 내부에 축적되어 유방암을 일으킬 수 있다는 사실이 밝혀졌다.Cosmetic preservatives make it possible to store cosmetics at room temperature for a long time. Cosmetics should be stored for a long time after opening, so put preservatives (preservatives) to protect consumers from being easily deteriorated. Preservatives that are mainly used in cosmetics include but are not limited to methylparaben, ethylyleparaben, propylparaben, butylparaben, quaternium-15, imidazolidinyl urea (Imidazolidinyl Urea). However, since cosmetics are used directly in the human body for a lifetime, even a small amount of preservatives can have a considerable effect on the human body. In fact, dermatologists say that 70 percent of patients who seek medical care for skin problems are cosmetically toxic (preservative). Preservative ingredients in cosmetics can cause allergic reactions or irritate the skin. Recently, it has been found that parabens, a kind of chemicals contained in various cosmetics and perfumes, accumulate in the human body and can cause breast cancer.
의약품 방부제로는 벤조산의 나트륨 염 등이 점안제, 수제(水劑), 주사제 등에 첨가되는데, 이러한 화학 방부제는 양이 초과되면 사람에게 치명적 해를 줄 수 있으므로 법(약사법 및 식품위생법)에 의해 그 종류와 사용량이 엄격히 통제되고 있다.As preservatives for medicines, sodium salt of benzoic acid is added to eyedrops, water agents, injections and the like. These chemical preservatives may give fatal effects to people if they are overproduced. Therefore, according to the law (Pharmaceutical Affairs Law and Food Sanitation Act) And usage are strictly controlled.
상기와 같은 화학방부제들은 인체 안전성에 관한 많은 문제점을 야기하므로, 인체 안전성 측면을 고려하면 자연의 생물로부터 추출하여 얻은 천연 방부제가 사용되는 것이 바람직하다. 지금까지 미생물 오염과 생장을 억제하는 천연 방부제로서 편백나무 추출물인 히노키티올(hinokitiol), 목련 추출물인 메그노놀(megnonol), 자몽종자 추출물인 DF-100 등이 개발되어 있으나 그 규모는 합성 보존제의 17 %에 불과하여 수요를 충족시키지 못하고 있다.Since the above-mentioned chemical preservatives cause many problems about human safety, it is preferable that natural preservatives obtained from natural organisms are used in consideration of human safety. So far, hinokitiol, megnonol, and grapefruit seed extract, DF-100, have been developed as natural preservatives that inhibit microbial contamination and growth. %, Which is not meeting demand.
사람의 피부색은 표피에 존재하는 색소세포인 멜라닌 세포에서 생성하는 피부멜라닌, 헤모글로빈이나 카로티노이드 등의 색소의 유무 및 피부의 두께와 반사도 등에 영향을 받는다. 이 중 피부색을 결정하는데 가장 중요한 요소인 멜라닌 색소는 인체에 정상적으로 존재하는 아미노산의 일종인 티로신(Tyrosine)이 멜라닌 세포 내에 존재하는 효소인 티로시네이즈(Tyrosinase)에 의해 도파(DOPA)가 되고, 계속되는 일련의 복잡한 산화과정을 통해 최종적으로 흑갈색의 중합체인 멜라닌을 생성하게 된다. 멜라닌 합성은 자외선 노출, 멜라노마(melanoma), 색소과다침착증(hyperpigmentation disease) 등의 요인에 의하여 합성이 촉진된다. 또한, 멜라닌 색소의 생합성은 티로시나제(tyrosinase) 효소를 비롯하여 여러 효소들에 의하여 조절되고 있으며, 그 중 티로시나제는 티로신(tyrosine)을 기질로 하여 L-도파퀴논(L-dopaquinone)으로 전이되는 초기 생합성과정 이후 디하이드록시인돌(dihydroxyindole)의 산화에 작용한다.The skin color of a person is influenced by the presence or absence of pigment such as skin melanin, hemoglobin or carotenoid produced in melanocytes, which are pigment cells existing on the epidermis, and thickness and reflectivity of the skin. Melanin pigment, which is the most important factor in determining the skin color, is a kind of amino acid normally present in the human body. Tyrosine is converted into DOPA by tyrosinase, an enzyme present in melanocytes, A series of complex oxidation processes ultimately produce melanin, a dark brown polymer. Synthesis of melanin is facilitated by factors such as ultraviolet light exposure, melanoma, hyperpigmentation disease, and the like. In addition, the biosynthesis of melanin pigment is regulated by various enzymes including tyrosinase enzyme, among which tyrosinase is an initial biosynthesis process which is transferred to L-dopaquinone using tyrosine as a substrate It then acts on the oxidation of dihydroxyindole.
그러므로 티로시나제 활성 억제제를 찾는 연구가 미백제의 개발에 있어서 중요한 부분을 차지하고 있으며, 현재 계속 알려지고 있는 티로시나제 저해제로 하이드로퀴논(hydroquinone), 4-하이드록시아니졸(4-hydroxyanisole), 아스코르빈산 (ascorbic acid) 유도체, 코지산(kojic acid), 아젤라인산(azelaic acid), 코르티코스테로이드(corticosteroid), 레티노이드(retinoids), 알부틴(arbutin), 카테킨(catechin) 등이 있으나, 이들의 안전성과 경제성 등의 문제점으로 사용에 있어서 어려움이 있다. Therefore, a search for tyrosinase inhibitors has been an important part of the development of whitening agents, and the currently known tyrosinase inhibitors include hydroquinone, 4-hydroxyanisole, ascorbic acid, acid derivatives, kojic acid, azelaic acid, corticosteroids, retinoids, arbutin, catechin, etc., but their safety and economic problems Which is difficult to use.
따라서 뛰어난 구강 질환 치료 효과, 방부 효과 또는 피부 미백 효과를 보이는 조성물의 개발이 필요하다.Therefore, it is necessary to develop a composition showing excellent oral disease treatment effect, preservative effect or skin whitening effect.
따라서 본 발명은 구강 질환 치료 효과, 방부 효과 또는 피부 미백 효과를 갖는 화합물을 포함하는 조성물을 제공하는데 그 목적이 있다.Accordingly, it is an object of the present invention to provide a composition comprising a compound having an oral treatment effect, a preservative effect or a skin whitening effect.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1의 화합물을 유효성분으로 포함하는 구강 질환 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating oral diseases, which comprises a compound of formula (1) as an active ingredient.
[화학식 1][Chemical Formula 1]
또한 본 발명은 상기 화학식 1의 화합물을 유효성분으로 포함하는 구강 질환 예방 또는 개선용 건강기능식품을 제공한다.The present invention also provides a health functional food for preventing or ameliorating oral diseases comprising the compound of Chemical Formula 1 as an active ingredient.
또한 본 발명은 상기 화학식 1의 화합물을 유효성분으로 포함하는 방부제 조성물을 제공한다.The present invention also provides a preservative composition comprising the compound of Formula 1 as an active ingredient.
또한 본 발명은 상기 화학식 1의 화합물을 유효성분으로 포함하는 피부 미백용 약학 조성물을 제공한다.The present invention also provides a pharmaceutical composition for skin whitening comprising the compound of Formula 1 as an active ingredient.
또한 본 발명은 상기 화학식 1의 화합물을 유효성분으로 포함하는 피부 미백용 화장료 조성물을 제공한다.The present invention also provides a cosmetic composition for skin whitening comprising the compound of formula (1) as an active ingredient.
또한 본 발명은 상기 화학식 1의 화합물을 유효성분으로 포함하는 피부 미백용 건강기능식품 조성물을 제공한다.The present invention also provides a health functional food composition for skin whitening comprising the compound of Formula 1 as an active ingredient.
본 발명은 스티피탈리드(stipitalide, 5,8-dihydroxy-1H-cyclohepta-[c]furan-1,6(3H)-dione)를 유효성분으로 함유하는 구강질환 예방 또는 치료용 약학 조성물 및 개선용 건강기능식품, 방부제 조성물, 피부 미백용 약학 조성물, 화장료 조성물 및 건강기능식품 조성물에 대한 것으로, 상기 스티피탈리드는 독성이 낮고 다양한 세균에 대한 항균력이 우수하여 구강관련 다양한 제품과 식품, 화장품 또는 의약품의 방부제로 유용하게 사용될 수 있다. 또한 멜라닌 합성에 대한 저해활성이 우수하여 미백 관련 제품 조성물로도 유용하게 사용될 수 있다.The present invention relates to a pharmaceutical composition and an improvement for preventing or treating oral diseases containing stipitalide (5,8-dihydroxy- 1 H -cyclohepta- [ c ] furan-1,6 ( 3H ) The present invention relates to a pharmaceutical composition for skin whitening, a cosmetic composition and a health functional food composition, which are low in toxicity and excellent in antibacterial activity against various bacteria, It can be useful as a preservative in medicine. Also, it has excellent inhibitory activity against melanin synthesis and can be usefully used as a whitening-related product composition.
도 1은 스티피탈리드(Stipitalide)의 핵자기공명(nuclear magnetic resonance, NMR) 분석 결과이고,
도 2는 스티피탈리드의 근적외선 vs 중적외선(Near Infrared vs. Mid Infrared) 분석 결과이고,
도 3 내지 도 5는 스티피탈리드의 구강 질환 관련 균의 생육 억제 활성을 확인한 결과이고,
도 6 은 멜라닌 생성세포인 Melan-a 세포에 스티피탈리드를 처리한 후 세포 독성을 확인한 결과이고,
도 7은 피부암 세포인 B16F10 세포에 스티피탈리드를 처리한 후 세포 독성을 확인한 결과이고,
도 8은 Melan-a 세포에 스티피탈리드를 처리한 후 멜라닌 합성 억제 효과를 확인한 결과이고,
도 9은 B16F10 세포에 스티피탈리드를 처리한 후 멜라닌 합성 억제 효과를 확인한 결과이다. FIG. 1 shows the results of nuclear magnetic resonance (NMR) analysis of Stipitalide,
FIG. 2 shows the results of Near Infrared vs. Mid Infrared analysis of near-infrared rays vs. stipulated lead,
FIGS. 3 to 5 are the results of confirming the activity of inhibiting the growth of bacteria associated with oral diseases of staphylolide,
FIG. 6 shows the results of confirming cytotoxicity after treating melanin-producing cells, Melan-a cells, with stipitolide,
FIG. 7 shows the cytotoxicity of B16F10 cells, which are skin cancer cells, after stipetalide treatment,
FIG. 8 shows the results of confirming the effect of inhibiting melanin synthesis after treating staphyllid with Melan-a cells,
Fig. 9 shows the results of confirming the effect of inhibiting melanin synthesis after treating staphyllid with B16F10 cells.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 발명자들은 곤충에서 유래된 곰팡이를 에틸 아세테이트(ethyl acetate)로 추출하고 이를 분리, 정제하여 얻은 물질의 활성을 평가하던 중, 이의 우식균을 비롯한 다양한 균에 대한 억제 활성과 멜라닌 생성 억제 활성을 확인하여 본 발명을 완성하였다.The inventors of the present invention have found that when fungi derived from an insect is extracted with ethyl acetate and the activity of the substance obtained by separating and purifying the extract is evaluated, the inhibitory activity against various bacteria such as the yeast strain and the melanin production inhibitory activity To complete the present invention.
상기 물질은 하기 화학식 1로 표시되는 스티피탈리드(stipitalide, 5,8-dihydroxy-1H-cyclohepta-[c]furan-1,6(3H)-dione)이며, 홀리카(Holik)와 쿠(Kuhr)의 논문(Miroslav Holik and Ivo Kuhr, J. Chem. Soc.,Chem. Commun. 1973. 65-66)에서 처음으로 화학적 구조가 보고되었지만, 이 물질의 생리활성 효능 효과에 대한 연구는 전무한 상태이다.The material is stipitalide (5,8-dihydroxy-1 H -cyclohepta- [c] furan-1,6 ( 3H ) -dione) represented by the following formula 1: Holik and Koo Kuhr) (Miroslav Holik and Ivo Kuhr, J. Chem. Soc., Chem. Commun., 1973. 65-66), but there is no study on the effect of this substance on the physiological activity to be.
[화학식 1][Chemical Formula 1]
본 발명의 일 실시예에 따르면, 상기 화학식 1로 표시되는 스티피탈리드는 우식균인 스트렙토코쿠스 뮤탄스(Streptococcus mutans) ATCC25175, 스트렙토코쿠스 소르비누스(Streptococcus sorbrinus) ATCC27607와 치주염 원인균인 포르피로모나스 긴기발리스(Porphyromonas gingivalis) ATCC33277, 구취 원인균인 푸소박테리움 누클리아툼(Fusobacterium nucleatum) ATCC23726, 폐렴간균(Klebsiella pneumoniae) ATCC15380의 생육을 효과적으로 억제하였다.According to one embodiment of the present invention, the staphorylid represented by the formula (1) is a Streptococcus mutans strain , ATCC 25175, Streptococcus sorbrinus < RTI ID = 0.0 > ATCC 27607 and Porphyromonas , a causative organism of periodontitis gingivalis ) ATCC33277, The bad breath causative organism, Fusobacterium nucleatum ) ATCC 23726 , Klebsiella pneumoniae pneumoniae ) The growth of ATCC15380 was effectively inhibited.
따라서 본 발명은 상기 화학식 1의 화합물을 유효성분으로 포함하는 구강 질환 예방 또는 치료용 약학 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for preventing or treating oral diseases, which comprises the compound of
상기 구강 질환은 치아우식증, 치주염 및 구취로 이루어진 군에서 선택된 어느 하나이나, 이에 제한되는 것은 아니다.The oral disease may be any one selected from the group consisting of dental caries, periodontitis and bad breath, but is not limited thereto.
상기 화학식 1의 화합물은 스티피탈리드(stipitalide)로 곤충유래 곰팡이균인 코디셉스 종(Cordyceps sp.)의 배양액으로부터 분리 정제한 것을 특징으로 한다.The compound of
상기 곤충유래 곰팡이인 코디셉스 종은 다른 곰팡이와 마찬가지로 그 성상이 변하기 쉬우며, 이의 돌연변이주, 형질융합체 또는 유전자 재조합체 모두 본 발명의 범위에 포함된다.The insect-derived fungus, Coryseps sp., Is susceptible to change in properties as with other fungi, and the mutant strain, transgenic fusant or genetic recombinant thereof is included in the scope of the present invention.
상기 곤충유래 곰팡이를 이용하여 스티피탈리드를 생산하기 위해서, 상기 균주를 통상 미생물이 이용하는 영양원을 함유하는 배지에서 배양한다. In order to produce stipepetalide using the insect-derived fungus, the strain is cultured in a medium containing a nutrient source commonly used by microorganisms.
영양원은 탄소원으로서 글루코스(glucose), 프락토스(fructose), 슈크로스(sucrose), 덱스트린(dextrin) 등을 사용하고, 질소원으로서 트립톤(tryptone), 콘스팁리쿼(corn steep liquor, CSL) 등을 사용한다. The nutrient sources include glucose, fructose, sucrose, dextrin, and tryptone, corn steep liquor (CSL), and the like as a nitrogen source. use.
배양방법으로는 호기적인 조건에서의 배양법, 특히 액침배양법이 적당하며, 배양은 26 ℃ 내지 30 ℃의 온도범위에서 수행한다.As the culture method, a culture method under aerobic conditions, particularly an immersion culture method, is suitable, and the culture is carried out at a temperature range of 26 to 30 캜.
배양이 완료된 후, 배양액을 흡착 크로마토그래피, 에틸 아세테이트 추출, 겔 여과 크로마트그래피 및 고압 액체 크로마토그래피 등의 과정을 통해 목적 화합물을 정제할 수 있다.After the cultivation is completed, the target compound can be purified through a process such as adsorption chromatography, ethyl acetate extraction, gel filtration chromatography and high pressure liquid chromatography.
더불어 본 발명은 상기 화학식 1의 화합물을 유효성분으로 포함하는 구강 질환 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving oral diseases, which comprises the compound of formula (1) as an active ingredient.
본 발명의 또 다른 실시예에 따르면, 상기 화학식 1로 표시되는 스티피탈리드는 사람 및 동물에 질병을 유발하는 균으로 알려진 맨하이미아 헤모리티카(Mannheimia haemolytica) ATCC43270MH, 파스튜렐라 멀토시다(Pasteurella multocida) ATCC43137PM, 엔테로코커스 패칼리스(Enterococcus faecalis) ATCC29212, 살모넬라 콜레라수이스(Salmonella choleraesuis), 살모넬라 수이(Salmonella sui), 살모넬라 티피무리움(Salmonella typhimurium), 스트렙토코커스 아갈락티애(Streptococcus agalactiae), 스트렙토코커스 유베리스(Streptococcus uberis), 스트렙토코커스 디스갈락티애(Streptococcus dysgalactiae), 살모넬라 엔타라이티디스(Salmonella enteritidi), 악티노바실루스 플뢰로뉴모니애(Actinobacillus pleuropneumoniae) ATCC27090, 히스토필루스 솜니(Histophilus somni) ATCC700025 및 스타필로코커스 뉴모니아(Staphylococcus neumoniae) ATCC49619의 생육을 억제하였으며, 특히 방부제 선발 시 지표가 되는 대장균(Escherichia coli) ATCC25922, 녹농균(Pseudomonas aeruginosa) ATCC27853 및 황색포도상구균(Staphylococcus aureus) ATCC29213의 생육도 억제하였다.According to another embodiment of the present invention, the stipitolide represented by the above formula (1) is a Mannheimia < RTI ID = 0.0 > haemolytica ) ATCC43270MH, Pasteurella multocida ATCC 43137PM , Enterococcus faecalis ) ATCC 29212, But are not limited to, Salmonella choleraesuis , Salmonella sui , Salmonella typhimurium , Streptococcus agalactiae , Streptococcus uberis , Streptococcus spp . Streptococcus dysgalactiae , Salmonella enteritidis , Actinobacillus pleuropneumoniae ATCC27090, Histophilus somni ) ATCC700025 and Staphylococcus neumoniae ATCC49619 were inhibited. Especially Escherichia coli ATCC25922, Pseudomonas sp. aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 29213 were also inhibited.
따라서 본 발명은 하기 화학식 1의 화합물을 유효성분으로 포함하는 방부제 조성물을 제공한다.Accordingly, the present invention provides a preservative composition comprising a compound of the following formula (1) as an active ingredient.
[화학식 1][Chemical Formula 1]
상기 화학식 1의 화합물은 스티피탈리드(stipitalide)로 곤충유래 곰팡이균인 코디셉스 종(Cordyceps sp.)의 배양액으로부터 분리 정제한 것이며, 식품, 화장품 또는 의약품에 사용될 수 있다.The compound of
본 발명의 또 다른 실시예에 따르면, 상기 화학식 1로 표시되는 스티피탈리드는 멜라닌 생성세포인 Melan-a 세포 및 피부암(흑색종) 세포인 B16F10 세포에 처리하였을 때 양성대조군인 알부틴(arbutin)과 유사한 수준의 멜라닌 합성 저해능을 보였다.According to another embodiment of the present invention, the stipulative ligand represented by the above formula (1) is a melanin-producing cell, melan-a cell and skin cancer (melanoma) cell, B16F10 cell, Showed a similar level of inhibition of melanin synthesis.
따라서 본 발명은 하기 화학식 1의 화합물을 유효성분으로 포함하는 피부 미백용 약학 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for skin whitening comprising the compound of formula (1) as an active ingredient.
[화학식 1][Chemical Formula 1]
상기 화학식 1의 화합물은 스티피탈리드(stipitalide)로 곤충유래 곰팡이균인 코디셉스 종(Cordyceps sp.)의 배양액으로부터 분리 정제한 것이다.The compound of
더불어 본 발명은 상기 화학식 1의 화합물을 유효성분으로 포함하는 피부 미백용 화장료 조성물을 제공한다.In addition, the present invention provides a cosmetic composition for skin whitening comprising the compound of
또한, 본 발명은 상기 화학식 1의 화합물을 유효성분으로 포함하는 피부 미백용 건강기능식품 조성물을 제공한다.The present invention also provides a health functional food composition for skin whitening comprising the compound of
본 발명에 따른 약학 조성물은 약학조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다.The pharmaceutical compositions according to the present invention may further comprise suitable carriers, excipients or diluents conventionally used in the production of pharmaceutical compositions.
본 발명에서 사용가능한 담체, 부형제 또는 희석제로는, 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등을 들 수 있다.Examples of the carrier, excipient or diluent which can be used in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.
본 발명에 따른 약학조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method .
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물은 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제할 수 있다. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose sucrose), lactose, gelatin, and the like.
또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included .
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.
본 발명에 따른 약학조성물의 유효성분인 스티피탈리드의 사용량은 환자의 나이, 성별, 체중, 질환에 따라 달라질 수 있으나, 0.001 내지 50 mg/kg으로, 바람직하게는 0.001 내지 5 mg/kg을 일일 1회 내지 수회 투여할 수 있다. The amount of stipitolide used as an active ingredient of the pharmaceutical composition according to the present invention may vary depending on the patient's age, sex, weight, and disease, but is preferably 0.001 to 50 mg / kg, more preferably 0.001 to 5 mg / It may be administered once or several times.
또한, 본 발명에 따른 스티피탈리드의 투여량은 투여경로, 질병의 정도, 성별, 체중, 나이 등에 따라서 증감될 수 있다. 따라서, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.Further, the dose of staphylolide according to the present invention may be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.
상기 약학조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 기관지내 흡입, 자궁내 경막 또는 뇌혈관내(intracerebroventricular) 주사에 의해 투여될 수 있다.The pharmaceutical composition may be administered to mammals such as rats, mice, livestock, humans, and the like in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intratracheal, intrauterine or intracerebroventricular injections.
더불어 본 발명에 따른 건강기능식품은 분말, 과립, 정제, 캡슐, 시럽 또는 음료의 형태로 제공될 수 있으며, 상기 건강기능식품은 유효성분인 스티피탈리드 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다. In addition, the health functional food according to the present invention may be provided in the form of powder, granules, tablets, capsules, syrups or beverages. The health functional food may be used in combination with food or food additives other than the active ingredient stapitalil, Can be suitably used according to the method of The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.
상기 건강기능식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등을 들 수 있다.There is no particular limitation on the kind of the above health functional food and examples thereof include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, , Drinks, alcoholic beverages and vitamin complexes.
또한 본 발명에 따른 화장료 조성물은 유효성분인 스티피탈리드 외에 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함할 수 있다.In addition, the cosmetic composition according to the present invention may contain conventional additives such as stabilizers, solubilizers, vitamins, pigments and flavors, and carriers in addition to the active ingredient stapital.
상기 화장료 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 세정제, 파우더, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 썬 크림, 유연 화장수, 수렴 화장수, 영양 화장수, 영양 크림, 마사지 크림, 에센스, 아이 크림, 팩, 스프레이, 세안제, 목욕제 또는 파우더의 제형으로 제조될 수 있다.The cosmetic composition may be prepared in any form conventionally produced in the art and may be prepared, for example, as a solution, suspension, emulsion, paste, gel, cream, lotion, detergent, powder, oil, powder foundation, emulsion A foundation, a wax foundation, a spray, and the like, but the present invention is not limited thereto. More specifically, it can be manufactured in the form of a sun cream, a flexible lotion, a convergent lotion, a nutritional lotion, a nutritive cream, a massage cream, an essence, an eye cream, a pack, a sprayer, a cleanser, a bath agent or a powder.
상기 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation is a paste, cream or gel, an animal oil, a vegetable oil, a wax, a paraffin, a starch, a tracer, a cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as a carrier component .
상기 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.When the formulation is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, chlorofluorohydrocarbons, propane / Or propellants such as dimethyl ether.
상기 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 용해 화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다. When the formulation is a solution or an emulsion, a solvent, a solubilizing agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, - butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid esters of sorbitan.
상기 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.When the formulation is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspension such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, a microcrystalline cellulose , Aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
<실시예 1> 스티피탈리드(Stipitalide) 생산Example 1 Production of Stipitalide
1) 코디셉스 종(Cordyceps sp.)인 CS429 배양 및 접종1) Culture and inoculation of CS429, Cordyceps sp.
먼저 SDA(sabourand dextrose agar)배지에 CS429를 접종하여 항온배양기(27℃, 1주)에서 배양하였다. 그 후 배양된 CS429의 5 조각(8mm×8mm)를 취하여 멸균된 액체배지 SDA에 접종하고, 항온진탕배양기(27℃, 180rpm)에서 4일간 배양하여 배양액을 얻었다.First, CS429 was inoculated into SDA (sabourand dextrose agar) medium and cultured in a constant temperature incubator (27 ° C, 1 week). Then, 5 pieces (8 mm x 8 mm) of the cultured CS429 were inoculated into sterilized liquid medium SDA and cultured in a constant temperature shaking incubator (27 DEG C, 180 rpm) for 4 days to obtain a culture solution.
2) 분리 및 정제2) Separation and purification
2-1) 충진제로 HP20을 이용한 1차 분리2-1) Primary separation using HP20 as a filler
상기 배양액 10 ml을 취한 후, 이를 원심분리기로 분리하여 균사체를 제거하고 상등액만을 취하였다. After taking 10 ml of the above culture, the mycelium was removed by centrifugation, and only the supernatant was taken.
이후 충진제로써 HP20(100mm×1300mm)을 이용하여 1차 분리를 실시하였다. Thereafter, primary separation was performed using HP20 (100 mm × 1300 mm) as a filler.
전개용매는 35% 에탄올로, 충진제 부피의 3배의 양으로 세척한 후 80% 에탄올로 충진제 부피의 4배로 전개하면서 활성분획을 수확하였다. The developing solvent was washed with 35% ethanol in an amount three times the volume of the filler, and then the active fraction was harvested while expanding to 4 times the volume of the filler with 80% ethanol.
이후 감압농축기를 사용하여 2차 오픈칼럼 크로마토그래피를 위해 최소한의 양으로 농축하여 농축액을 제조하였다.The concentrate was then concentrated to a minimum amount for secondary open column chromatography using a vacuum concentrator to prepare a concentrate.
2-2) 실리카 겔을 이용한 2차 분리2-2) Secondary separation using silica gel
상기 실시예 1 중 2-1)에서 제조한 농축액을 충진제로써 실리카겔(silica gel; 55mm×800mm, 0.40~0.63㎛)을 이용하여 2차 분리 및 정제를 실시하여 활성분획을 획득하였다.The concentrate prepared in 2-1) of Example 1 was subjected to secondary separation and purification using a silica gel (55 mm x 800 mm, 0.40 to 0.63 m) as a filler to obtain an active fraction.
전개용매는 클로로포름(chloroform)과 에틸 아세테이트(ethyl acetate)를 100:10, 100:20 또는 100:30으로 제조하여 순서대로 전개하여 활성분획을 수집하였다.Chloroform and ethyl acetate were prepared at 100: 10, 100: 20 or 100: 30, and the active fractions were collected.
상기 수집된 분획은 고성능 액체 크로마토그래피(HPLC, shimadzu LC-6AD)를 이용하여 분석하였다. The collected fractions were analyzed using high performance liquid chromatography (HPLC, shimadzu LC-6AD).
분석조건은 Shim-pack Prep-ODS(H) Kit 250mm×20mm 컬럼으로 개미산(formic acid)와 아세토니트릴(acetonitrile)용매를 혼합하여 사용하였다. The analytical conditions were a Shim-pack Prep-ODS (H) Kit 250 mm × 20 mm column, mixed with formic acid and acetonitrile solvent.
유속 0.5ml/분, 상온, 검출기는 PDA(shimadzu SPD-M10Avp)를 사용하여 스티피탈리드를 순수분리하였고 용매를 감압건조기로 제거한 후 냉동건조하여 분말로서 스티피탈리드를 얻었다.The stipetal lead was purified by using a PDA (shimadzu SPD-M10Avp) at a flow rate of 0.5 ml / min at room temperature, and the solvent was removed by a reduced pressure dryer, followed by freeze drying to obtain stipepetal lead as a powder.
3) 스티피탈리드의 구조분석3) Structural analysis of stipitol lead
상기 실시예 1 중 2-2)에서 제조한 스티피탈리드 시료를 NMR용 용매 CDCl3에 녹인 후 5㎜ 튜브에 넣어(Varian Inova-300) NMR분석을 하였고, 그 결과를 도 1 및 2에 나타내었다. 이때 내부 표준시약으로 테트라메틸살린(tetra methyl silane, TMS)을 사용하였다.The staphthalaldehyde prepared in 2-2) of Example 1 was dissolved in a solvent for NMR, CDCl 3 , and placed in a 5 mm tube (Varian Inova-300) for NMR analysis. The results are shown in FIGS. 1 and 2 . At this time, tetramethyl silane (TMS) was used as an internal standard reagent.
질량분석 및 NMR 스펙트럼 분석 결과를 해석한 결과, 상기 2-2)에서 제조한 물질은 C9H6O5의 분자식을 가지며, 하기 화학식 1의 구조를 가진 스티피탈리드(stipitalide, 5,8-dihydroxy-1H-cyclohepta-[c]furan-1,6(3H)-dione)임을 알 수 있었다.Mass spectrometry and NMR spectrum analysis showed that the material prepared in 2-2) had a molecular formula of C 9 H 6 O 5 and stipitalide (5,8- dihydroxy-1 H -cyclohepta- [ c ] furan-1,6 (3 H ) -dione).
[화학식 1][Chemical Formula 1]
<실시예 2> 스티피탈리드의 항균 활성 확인Example 2 Confirmation of Antifungal Activity of Staphthalaldehyde
상기 실시예 1 중 2-2)에서 제조한 스티피탈리드의 항균 활성을 확인하기 위하여, 하기 표 1과 같이 almarBlue®(A Bio-Rad Company, USA) 방법을 수행하였다.The Example 1 of the styryl prepared in 2-2) in order to determine the antimicrobial activity of the lead Hospital, almarBlue ® as follows in Table 1 (A Bio-Rad Company, USA) method was performed.
2번 웰을 제외한 11개의 웰에 실험하고자 하는 대상균에 적합한 배지 100μl씩 분주하였고 12번 웰에는 200μl의 배지를 분주하였다. 디메틸 설폭시화물(Dimethyl sulfoxide, DMSO)에 스티피탈리드를 200μg/ml가 되게 용해시킨 후 1, 2, 3번 웰에 100μl씩 각각 분주하여 배지와 잘 혼합하였다. 3번 웰에서 100μl을 취하여 4번 웰에 분주하여 스티피탈리드 농도가 1/2로 희석되게 하였고 이러한 방법으로 10번 웰까지 연속으로 1/2씩 희석되게 하였으며 11번과 12번 웰에는 첨가하지 않았다. 1번, 2번 또는 12번 웰을 음성 대조군으로 사용하였고 11번 웰은 양성 대조군으로 사용하였다. 더불어 실험하고자 하는 균은 집락형성단위(Colony Forming Unit, CFU)가 1,000/ml이 되게끔 희석하고 1번과 12번 웰을 제외한 나머지 웰에 100μl씩 분주하여 각 웰의 최종 부피 200μl가 되게 하였다. 100 μl of the medium was dispensed into 11 wells except the No. 2 well, and 200 μl of the medium was dispensed into the 12 wells. Dimethyl sulfoxide (DMSO) was added to dimethyl sulfoxide Staphitalol was dissolved to a concentration of 200 μg / ml, and 100 μl of each solution was dispensed into
혐기성 균은 CO2 배양기에서 배양하였고 호기성 균은 일반 항온 배양기에서 37℃에서 3일간 충분히 배양한 후 almarBlue 시약 20μl를 각각의 웰에 분주하여 10분동안 상온에서 발색반응을 유도하였다. 균의 생육 유무는 각각의 웰의 내용물이 붉은색으로 변하면 균이 생육한 것이고 푸른색으로 유지되면 생육이 억제되는 것으로 구분하였다. 따라서 붉은색으로 변하기 시작하는 농도를 균의 최소억제 농도(Minimum Inhibition Concentration, MIC)로 결정하였다.The anaerobic bacteria were cultured in a CO 2 incubator. The aerobic bacteria were cultured for 3 days at 37 ° C in a normal temperature incubator, and
1) 구강 질환 관련 균의 생육 억제 활성 확인1) Confirming the growth inhibition activity of bacteria related to oral diseases
그 결과 도 3 내지 도 5에 나타난 바와 같이, 주요 우식균인 스트렙토코쿠스 뮤탄스 ATCC25175, 스트렙토코쿠스 소르비누스 ATCC27607에 대한 스티피탈리드의 MIC는 50μg/ml이었다. 더불어 주요 치주염 유발균인 포르피로모나스 긴기발리스 ATCC33277에 대한 MIC는 25μg/ml이었고, 주요 구취 유발균인 푸소박테리움 누클리아툼 ATCC23726, 폐렴간균 ATCC15380에 대한 MIC는 각각 50μg/ml, 6.25μg/ml인 것으로 확인되었다.As a result, as shown in FIG. 3 to FIG. 5, the MIC of streptokocus mutans ATCC 25175, Streptococcus sorbinus ATCC 27607 was 50 μg / ml. In addition, the MIC for the major periodontitis causing bacteria, Porphyromonas gingivalis ATCC33277 was 25 μg / ml, and the MICs for the major bad odor inducing bacteria, Fusobacterium nociliatum ATCC 23726 and pneumococcal ATCC 15380 were 50 μg / ml and 6.25 μg / ml < / RTI >
2) 그 외 균의 생육 억제 활성 확인2) Confirming growth inhibition activity of other bacteria
더불어 방부제 선발 시 지표가 되는 세균인 대장균 ATCC25922, 녹농균 ATCC27853, 황색포도상구균 ATCC29213에 대한 MIC와 그 외 동물 및 사람에게 병을 유발하는 세균에 대한 MIC는 하기 표 2에 나타내었다.In addition, the MICs for the Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 29213, which are indicators for selection of preservatives, and the MICs for other animal and human disease causing bacteria are shown in Table 2 below.
상기 실시예 1 및 실시예 2에서 확인한 바와 같이, 곤충에서부터 분리된 곰팡이균인 코디셉스 종의 배양액으로부터 분리 정제된 스티피탈리드는 충치, 치주염, 구취 유발균 뿐만 아니라 방부제 선발 시 지표로 사용되고 있는 진균, 세균 및 동물 병원성 세균에 항균력이 뛰어나 화장품, 식품, 의약품 등에 유용하게 이용될 수 있다.As confirmed in Examples 1 and 2 above, staphyllides isolated from the culture medium of the Codisps sp. Isolates from the insects were not only the fungal, periodontal, and odor-inducing bacteria, but also fungi , It is excellent in antibacterial activity against bacteria and animal pathogenic bacteria and can be used for cosmetics, foods, medicines and the like.
<실시예 3> 스티피탈리드의 세포독성 및 미백 효과 확인Example 3: Confirmation of cytotoxicity and whitening effect of stipitolide
1) 세포독성 시험1) Cytotoxicity test
스티피탈리드의 세포독성은 최대허용농도(maximum permissible concentration, MPL)를 산출하여 평가하였다.Cytotoxicity of staphorylid was evaluated by calculating the maximum permissible concentration (MPL).
이를 위하여 멜라닌 생성세포인 Melan-a(C57BL/6 마우스에서 유래, Dr. Bennett(Cancer Research Center, London, England)으로부터 분양)와 피부암(흑색종) 세포인 B16F10(한국세포주은행(KCLB)으로부터 분양)을 사용하였다.For this, Melan-a, a melanocyte-derived cell (derived from C57BL / 6 mouse, sold from Dr. Bennett (Cancer Research Center, London, England)) and skin cancer (melanoma) cell, B16F10 ) Were used.
Melan-a 세포주는 10% 소태아혈청(fetal bovine serum, FBS)과 1% 페니실린/스트렙토마이신(penicillin/streptomycin, P/S), 200 nM TPA(12-O-tetradecanoylphorbol-13-acetate)가 함유된 RPMI-1640 배지를 사용하여 37℃, 5% CO2조건의 배양기에서 배양하였으며 B16F10 세포주는 10% FBS와 1% P/S가 함유된 DMEM 배지를 사용하여 37℃, 5% CO2조건의 배양기에서 배양하였다.Melan-a cells were cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), 1% penicillin / streptomycin (P / S) and 200 nM TPA (12-O-tetradecanoylphorbol- the RPMI-1640 by using the culture medium was incubated in an incubator of 37 ℃, 5% CO 2 conditions B16F10 cell line was 10% FBS and 1% P / 37 ℃ S by using a DMEM medium containing, 5% CO 2 conditions Lt; / RTI >
스티피탈리드가 Melan-a 세포와 B16F10 세포에 미치는 독성을 알아보기 위해 알부틴(arbutin) 100μg/ml과 스티피탈리드 50, 60, 70, 80, 90 및 100μg/ml을 각각 처리하고 2일간 배양한 후 540 nm에서 흡광도를 측정하였다.To investigate the toxicity of staphorylid on Melan-a and B16F10 cells, 100 μg / ml of arbutin and 50, 60, 70, 80, 90 and 100 μg / ml of stipetal lead were treated and incubated for 2 days The absorbance was measured at 540 nm.
그 결과 도 6에서 나타낸 바와 같이, Melan-a 세포의 세포생존율은 알부틴 100μg/ml 처리시 101.604 ± 0.560%로 나타났으며, 스티피탈리드 50μg/ml 처리시 100.118 ± 1.769%, 60μg/ml에서는 88.294 ± 8.738%, 70μg/ml에서는 86.837 ± 5.251%, 80μg/ml에서는 88.598 ± 4.557%, 90μg/ml에서는 89.962 ± 6.474%, 100μg/ml에서는 83.581 ± 3.673%로 나타났다. 그러므로 시험범위 내에서 모두 80%이상의 생존율을 보여 세포독성이 나타나지 않았음을 알 수 있었다.As a result, as shown in FIG. 6, the cell survival rate of Melan-a cells was 101.604 ± 0.560% at 100 μg / ml of arbutin, 100.118 ± 1.769% at 50 μg / ml of staphylolide, and 88.294 Ml at 90 μg / ml, 83.581 ± 3.673% at 100 μg / ml, and 86.837 ± 5.251% at 70 μg / ml, 88.598 ± 4.557% at 80 μg / ml, Therefore, the survival rate was over 80% in all of the test ranges, indicating no cytotoxicity.
더불어 도 7에서 나타낸 바와 같이 B16F10 세포의 세포생존률은 알부틴 100μg/ml 처리시 100.760 ± 1.245%로 나타났으며, 스티피탈리드 50μg/ml 처리시 98.983 ± 5.254%, 60μg/ml에서는 100.873 ± 8.493%, 70μg/ml에서는 95.341 ± 1.325%, 80μg/ml에서는 87.584 ± 0.3%, 90μg/ml에서는 87.167 ± 6.707%, 100μg/ml에서는 86.3 ± 2.332%로 나타났다. 그러므로 시험범위 내에서 모두 80% 이상의 생존율을 보여 세포독성이 나타나지 않았음을 알 수 있었다.As shown in FIG. 7, the cell survival rate of B16F10 cells was 100.760 ± 1.245% at 100 μg / ml of arbutin, 98.983 ± 5.254% at 50 μg / ml of staphylolide, 100.873 ± 8.493% at 60 μg / The percentages were 95.341 ± 1.325% at 70 μg / ml, 87.584 ± 0.3% at 80 μg / ml, 87.167 ± 6.707% at 90 μg / ml and 86.3 ± 2.332% at 100 μg / ml. Therefore, the survival rate was over 80% in all of the test ranges, indicating no cytotoxicity.
2) 멜라닌 합성 저해능에 의한 미백효과 확인2) Confirm the whitening effect by melanin synthesis inhibition
Melan-a 세포주는 10% FBS와 1% P/S, 200 nM TPA가 함유된 RPMI-1640 배지를 사용하여 37℃, 5% CO2조건의 배양기에서 배양하였으며 B16F10 세포주는 10% FBS와 1% P/S가 함유된 DMEM 배지를 사용하여 37℃, 5% CO2조건의 배양기에서 배양하였다.Melan-a cell lines were cultured in RPMI-1640 medium containing 10% FBS, 1% P / S and 200 nM TPA in an incubator at 37 ° C and 5% CO 2. B16F10 cells were cultured in RPMI 1640 medium supplemented with 10% The cells were cultured in a DMEM medium containing P / S at 37 ° C and 5% CO 2 .
Melan-a 세포와 B16F10 세포를 48-웰 플레이트에 적정세포수(2×104 cells/well)만큼 분주하고 37℃, 5% CO2조건의 배양기에서 24시간 배양한 후 알부틴 100μg/ml과 스티피탈리드를 농도별(50, 60, 70, 80, 90 및 100μg/ml)로 1차 처치하여 72시간 배양하였다. 배양 후 PBS로 세척하고 다시 동일한 시료의 농도로 2차 처치하여 72시간 배양하고 1N NaOH 용액으로 멜라닌을 용해하여 ELISA 리더기로 490 nm에서 흡광도를 측정하였다. 측정된 흡광도를 기반으로 하기 수학식 1을 통하여 멜라닌 함량을 산출하였다.Melan-a cells and B16F10 cells were plated on a 48-well plate at an appropriate number of cells (2 × 10 4 cells / well) and cultured in an incubator at 37 ° C. and 5% CO 2 for 24 hours.
[수학식 1][Equation 1]
멜라닌 양(%)=(시료 첨가구의 흡광도/시료 무 첨가구의 흡광도)×100Amount of melanin (%) = (absorbance of sample added / absorbance of sample not added) x 100
그 결과 도 8과 같이, Melan-a 세포에서 시료를 처치하지 않은 음성 대조군과 비교할 때 양성 대조군인 알부틴을 100μg/ml 처리시 65.2 ± 2.6%의 멜라닌 함량을 보였고, 스티피탈리드는 50μg/ml에서 72.2 ± 5.5%, 60μg/ml에서 71.8 ± 4.8%, 70μg/ml에서 69.5 ± 3.8%, 80μg/ml에서 68.8 ± 5.3%, 90μg/ml에서는 67.6 ± 2.4%, 100μg/ml에서는 69.6 ± 2.4%의 멜라닌 함량을 보였다. 따라서 스티피탈리드는 양성대조군인 알부틴과 유사한 수준의 멜라닌 합성 저해능을 보이는 것을 확인하였다.As a result, Melan-a cells showed 65.2 ± 2.6% melanin content when 100 μg / ml of arbutin, a positive control group, was compared with a negative control sample without samples. Melanin content of staphylolide was 50 μg / ml , 72.6 ± 5.5%, 70.8 ± 4.8% at 60 μg / ml, 69.5 ± 3.8% at 70 μg / ml, 68.8 ± 5.3% at 80 μg / ml, 67.6 ± 2.4% at 90 μg / ml and 69.6 ± 2.4% at 100 μg / Melanin content. Therefore, it was confirmed that staphyllide showed a similar level of inhibition of melanin synthesis to that of positive control group arbutin.
더불어 도 9와 같이, B16F10 세포에서 시료를 처치하지 않은 음성 대조군과 비교할 때 양성 대조군인 알부틴을 100μg/ml 처리시 56.0 ± 1.9%의 멜라닌 함량을 보였고, 스티피탈리드는 50μg/ml에서 66.0 ± 4.4%, 60μg/ml에서 64.4 ± 3.9%, 70μg/ml에서 64.3 ± 5.5%, 80μg/ml에서 61.0 ± 3.8%, 90μg/ml에서 55.1 ± 2.7%, 100μg/ml에서는 60.9 ± 4.0%의 멜라닌 함량을 보였다. 따라서 스티피탈리드는 양성대조군인 알부틴과 유사한 수준의 멜라닌 합성 저해능을 보이는 것을 확인하였다.In addition, as shown in Fig. 9, melanin content of 56.0 ± 1.9% was shown when 100 μg / ml of arbutin, a positive control, was compared with a negative control sample not treated with B16F10 cells. Staphyllide showed 66.0 ± 4.4 , 60.4 ± 3.9% at 60 μg / ml, 64.3 ± 5.5% at 70 μg / ml, 61.0 ± 3.8% at 80 μg / ml, 55.1 ± 2.7% at 90 μg / ml and 60.9 ± 4.0% at 100 μg / ml It looked. Therefore, it was confirmed that staphyllide showed a similar level of inhibition of melanin synthesis to that of positive control group arbutin.
상기 실시예 3에서 살펴본 바와 같이, 곤충에서부터 분리된 곰팡이균인 코디셉스 종에서 분리 정제된 스티피탈리드는 멜라닌 합성을 억제하는 효과가 뛰어나 의약품, 화장품, 건강기능식품 등에 미백 효과를 위한 용도로 유용하게 이용될 수 있다.As described in Example 3 above, the staphylolide isolated and purified from the Codiscept sp. Isolating from the insect is excellent for inhibiting melanin synthesis and is useful as a whitening effect in medicines, cosmetics, health functional foods, etc. Lt; / RTI >
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질직인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the present invention be defined by the appended claims and their equivalents.
Claims (4)
[화학식 1]
A pharmaceutical composition for skin whitening comprising a compound of the following formula (1) as an active ingredient.
[Chemical Formula 1]
[화학식 1]
A cosmetic composition for skin whitening comprising a compound of the following formula (1) as an active ingredient.
[Chemical Formula 1]
[화학식 1]
A health functional food composition for skin whitening comprising a compound of the following formula (1) as an active ingredient.
[Chemical Formula 1]
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